Targeting of c-kit+ hematopoietic progenitor cells prevents hypoxic pulmonary hypertension

Hematopoietic c-kit+ progenitor cells may contribute to pulmonary vascular remodeling and pulmonary hypertension. Stromal derived factor-1 (SDF-1/CXCL12) and its receptors CXCR4 and CXCR7 have been shown to be critical for homing and mobilization of hematopoietic c-kit+ progenitor cells in the perivascular niche. We administered AMD3100, a CXCR4 antagonist, and CCX771, a CXCR7 antagonist, to chronic hypoxia exposed mice in order to study the role of c-kit+ progenitor cells in pulmonary hypertension. CXCL12, CXCR4 and CXCR7 protein expression, hemodynamic parameters, right ventricular mass, extent of vascular remodeling and perivascular progenitor cell accumulation were studied. Chronic hypoxia-exposed mice showed increased total lung tissue expression of CXCR4, CXCR7 and CXCL12 after development of pulmonary hypertension. This was associated with significantly increased right ventricular systolic pressure, and evidence of right ventricular hypertrophy, vascular remodeling and perivascular c-kit+/sca-1+ progenitor cell accumulation. CCX771 administration did not abrogate these effects. In contrast, administration of AMD3100, whether alone or combined with CCX771, prevented vascular remodeling, pulmonary hypertension and perivascular accumulation of c-kit+/sca-1+ progenitor cells, with a synergistic effect of these agents. This study offers important pathophysiological insights into the role of hematopoietic c-kit+ progenitors in hypoxia-induced vascular remodeling and may have therapeutic implications for pulmonary hypertension. Word count: 198 words